A number of recent
preclinical studies have sparked interest in the concept of exploiting
conventional chemotherapeutic drugs as antiangiogenics. Such
antiangiogenic activity is achieved or optimized by metronomic-dosing
protocols in which the drug is given at comparatively low doses using a
frequent schedule of administration (e.g., once to three times per
week) with no breaks, particularly when combined with an endothelial
cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic
drugs is particularly suitable for this type of treatment strategy.
We
tested one such drug, cyclophosphamide (CTX), in a protocol wherein the
drug was administered to mice at low doses, of approximately 10-40
mg/kg on a daily basis through the drinking water. CTX is typically
given p.o. to patients, but it has almost always been injected when
treating preclinical mouse tumor models. We found p.o. CTX to be a safe
and convenient treatment with significant antitumor efficacy. Growth
delays were observed for human orthotopic breast or ectopic colon
cancer xenografts in nude or SCID mice. Established PC3 human prostate
tumor xenografts could be induced to almost fully regress, remaining
virtually nonpalpable for > or =2 months of continuous therapy,
after which tumors began to grow progressively.
These re-emergent
tumors were not found to be drug resistant when tested in new hosts,
using the same treatment protocol. Regression of spontaneously arising,
late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice
was also observed. The effects of continuous p.o. CTX treatment were
enhanced significantly in an orthotopic, metastatic breast cancer
xenograft model when used in combination with an antivascular
endothelial growth factor receptor-2 blocking antibody.
Maximum
tolerated dose levels established for other mouse strains proved highly
toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were
well tolerated. Taken together, the results demonstrate the feasibility
of delivering CTX in a p.o. metronomic chemotherapy regimen, which
proved safe, reasonably efficacious, and potentially applicable to
chronic treatment. Such a regimen may be particularly well suited for
integration with antiangiogenic drugs.